Novel Ruthenium and Osmium Nitrosyl and Nitroxide Complexes

Nitric oxide (NO) was considered for a long time as a gas with bad reputation, which was suspected to be a carcinogen, a pollutant able to destroy ozone or a precursor of acid rain. All this can be explained by high reactivity of this free-radical molecule. From the coordination chemist point of view NO like other small molecules or ions such as CO or CN - was supposed to bind irreversibly to metal ions acting as a poison. Surprising is, therefore, that this molecule has so many beneficial physiological effects, playing a key role in signal transduction and cytotoxicity, muscle relaxation leading to decrease of blood pressure, cell self-defence against pathogens, etc. Two ruthenium complexes, viz., trans-[RuIIICl 4 (L)(L`)] - (L = L` = indazole = Hind) for KP1019, and (L = imidazole, L`= DMSO) for NAMI-A, recently finished successfully phase I clinical trials, the first as an anticancer agent against primary tumours and metastases, and, in particular, colon carcinomas, and the second as an antimetastatic drug. NAMI-A is currently entering phase II clinical trials in Great Britain. The mechanism of metastases control of NAMI-A was suggested to be attributed to the combined effects of anti-angiogenic and anti- invasive properties of this drug candidate on tumour cells and blood vessels. The pronounced control of angiogenesis is probably due to the scavenging properties of NAMI-A on the NO produced by the endothelial cells. Since KP1019 developed in our laboratory possesses low general toxicity that implies its ability to accumulate in tumour cells via transferrin-cycle as a viable pathway for the selective delivery of cytotoxic drugs we intend to use this fact and prepare ruthenium-azole-chlorido-nitrosyl compounds related to KP1019, in which one chloride ligand is substituted by NO, and the number of azole ligands varies from one to four, and investigate their antiproliferative activity and ability to release NO after reduction in tumour cells by cellular reductants. Investigation of analogous osmium-azole-chlorido-nitrosyl compounds is of particular interest as well, not only as complementing the rapidly growing spectrum on useful ruthenium nitrosyls, but also because of well established differences between the two metals, reflected in preparation approaches for ruthenium- and osmium-nitrosyls, on the preference for higher oxidation states and on stronger p back donation from lower oxidation states, as well as on the much stronger spin-orbit coupling of the heavier congener. Complexes of azole-substituted nitroxide free radicals will be also synthesised as spin probe to monitor the distribution of the drug within tumour cells or mimic nitrosyl coordination.

Nitric oxide (NO) was considered for a long time as a gas with bad reputation, which was suspected to be a carcinogen, a pollutant able to destroy ozone or a precursor of acid rain. All this can be explained by high reactivity of this free-radical molecule. From the coordination chemist point of view NO is a redox-active ligand supposed to bind irreversibly to metal ions acting as a poison. Therefore, it is surprising, that this molecule has so many beneficial physiological effects, playing a key role in signal transduction and cytotoxicity, muscle relaxation leading to decrease of blood pressure, cell self-defense against pathogens, etc. The mechanism of metastases control of NAMI-A, an investigational drug in clinical trials, was suggested to be attributed to the combined effects of its anti-angiogenic and anti-invasive properties on tumor cells and blood vessels. The pronounced control of angiogenesis is supposed to be due to the scavenging properties of NAMI-A on the NO produced by the endothelial cells. Since KP1019, another anticancer drug in clinical trials, possesses low general toxicity and enhanced selectivity for cancer cells, we intended to use this fact and prepare ruthenium-azole-chlorido-nitrosyl compounds related to KP1019, in which one chloride ligand is substituted by NO, and the number of azole ligands varies from one to four, and investigate their antiproliferative activity and ability to release NO after reduction in tumor cells by cellular reductants. Investigation of analogous osmium-azole-chlorido-nitrosyl compounds is of particular interest as well, not only as complementing the rapidly growing spectrum on useful ruthenium nitrosyls, but also because of well established differences between the two metals. We succeeded to synthesize a large family of metal-nitrosyl complexes of the general formula (cation)[MCl4(Hazole)(NO)], where cation = Na+, nBu4N+, H2azole+, M = Ru, Os and Hazole = 1H-pyrazole, 1H-indazole, 1H-imidazole and 1H-benzimidazole, as cis and trans isomers, and studied the effect of the Ru vs Os, cis-trans isomerism, azole heterocycle and counter ion identity on their antiproliferative activity. An unprecedented difference in cytotoxicity for chemically related pairs of ruthenium and osmium complexes has been found. In addition, a hypothetical metabolite of KP1019, namely mer,trans-[RuCl3(Hind)(NO)] has been prepared and its electronic structure described in detail. Moreover, the reactivity of osmium-nitrosyl complexes towards amino acids, the most important small molecular weight biological ligands, has been investigated and new products isolated and comprehensively characterized. Such studies may shed light on the difference on cytotoxicity of ruthenium- and osmium-nitrosyl complexes with azole heterocycles.